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<p>Enhancers, as <i>cis</i>-regulatory elements, play pivotal roles in transcriptional homeostasis. The abnormality in enhancers is highly associated with various diseases, including osteoporosis. However, the landscape of active enhancers underlying bone diseases remains incomplete. By conducting an integrative analysis of transcriptome and ChIP-seq data, we identify enh11 as an active enhancer during osteoblastogenesis. CRISPR/Cas9-mediated deletion of enh11 inhibits cell differentiation of pre-osteoblast MC3T3-E1 cells. The osteoblast-specific knockout of enh11 reduces bone formation and decreases bone mass in mice. In addition, <i>Etv4</i> is identified as the downstream target of enh11. Functional experiments both in vitro and in vivo validate that <i>Etv4</i> promotes osteogenesis and bone formation. Mechanistically, enh11 upregulates the expression of <i>Etv4</i> to promote osteogenesis, probably via binding to the transcription factor Stat3. These findings not only deepen our comprehension of the molecular mechanisms of enh11 underlying bone formation but also highlight enh11 and <i>Etv4</i> as promising therapeutic targets for osteoporosis.</p>

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Enhancer-mediated Etv4 activation stimulates osteogenic differentiation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Junyou Zhang,
  • Qilin Wang,
  • Zhuoyu Cheng,
  • Jiaxin Liu,
  • Qian Liu,
  • Sihan Qi,
  • Zhiheng Chen,
  • Yingying Duan,
  • Zhaoshuo Liu,
  • Jie Jia,
  • Chunyan Li

摘要

Enhancers, as cis-regulatory elements, play pivotal roles in transcriptional homeostasis. The abnormality in enhancers is highly associated with various diseases, including osteoporosis. However, the landscape of active enhancers underlying bone diseases remains incomplete. By conducting an integrative analysis of transcriptome and ChIP-seq data, we identify enh11 as an active enhancer during osteoblastogenesis. CRISPR/Cas9-mediated deletion of enh11 inhibits cell differentiation of pre-osteoblast MC3T3-E1 cells. The osteoblast-specific knockout of enh11 reduces bone formation and decreases bone mass in mice. In addition, Etv4 is identified as the downstream target of enh11. Functional experiments both in vitro and in vivo validate that Etv4 promotes osteogenesis and bone formation. Mechanistically, enh11 upregulates the expression of Etv4 to promote osteogenesis, probably via binding to the transcription factor Stat3. These findings not only deepen our comprehension of the molecular mechanisms of enh11 underlying bone formation but also highlight enh11 and Etv4 as promising therapeutic targets for osteoporosis.